Apolipoprotein (apo) E plays critical roles in lipid and lipoprotein metabolism both extracellularly and intracellularly. Recent studies in our laboratories have shown that internalized apoE may be spared from degradation and recycled, a process that would enable apoE to impact cellular functions. It is the objective of this grant to define the mechanisms of apoE recycling and resecretion and to start addressing its physiologic relevance. This proposal will test the working hypothesis that a fraction of internalized apoE is spared degradation in the cell and recycled, providing a mechanism whereby a protein that is critical for many biological processes can maximize its impact on cellular functions. This hypothesis will be tested through the following specific aims: Specific Aim #1. To determine if apoE recycling is dependent upon cellular entry point or the lipoprotein particle with which apoE is associated. These studies will test the hypothesis that the disposition of internalized apoE and the potential for recycling are dependent on the particle on which apoE resides and the point of entry into the cell. Specific Aim #2. To define the intracellular trafficking pathway of recycling apoE. These studies will test the hypothesis that apoE recycles through the secretory pathway, specifically through the Golgi apparatus. Specific Aim #3. To define the physiologic relevance of apoE recycling. These studies will test the hypothesis that recycling provides a pathway for apoE to impact cellular functions, specifically lipid and lipoprotein metabolism, secretion-capture, and cholesterol efflux. These studies will primarily focus on apoE recycling by the hepatocyte, but will also expand to the macrophage, a cell type for which the impact of apoE recycling on function may be of great relevance to atherogenesis.